Preclinical antitumor activity and pharmacological properties of deoxyspergualin

A new antibiotic, deoxyspergualin (DSG), demonstrated antitumor activity against L1210 leukemia in mice. The life span of mice bearing either i.p. or s.c.-implanted L1210 increased greater than 150% following i.p. administration of 25 mg/kg DSG on days 1-9. Activity obtained with i.p. bolus treatmen...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 1987-02, Vol.47 (3), p.685-689
Main Authors: PLOWMAN, J, HARRISON, S. D. JR, TRADER, M. W, GRISWOLD, D. P. JR, CHADWICK, M, MCCOMISH, M. F, SILVEIRA, D. M, ZAHARKO, D
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Antibiotics, Antineoplastic - therapeutic use
Antineoplastic agents
Biological and medical sciences
Drug Administration Schedule
Drug Evaluation, Preclinical
General aspects
Guanidines - administration & dosage
Guanidines - therapeutic use
Injections, Intraperitoneal
Injections, Intravenous
Medical sciences
Mice
Mice, Inbred Strains
Pharmacology. Drug treatments
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Summary:A new antibiotic, deoxyspergualin (DSG), demonstrated antitumor activity against L1210 leukemia in mice. The life span of mice bearing either i.p. or s.c.-implanted L1210 increased greater than 150% following i.p. administration of 25 mg/kg DSG on days 1-9. Activity obtained with i.p. bolus treatments was schedule dependent. The tumor burden in mice bearing the s.c. implanted L1210 was reduced by 4-6 log10 units at the end of treatment when DSG was administered every 3 h for 8 injections on days 1, 5, and 9. By contrast, single injections of DSG on days 1, 5, and 9 allowed the tumor burden to increase at least 100-fold during treatment and daily single injections for 9 days reduced the tumor burden by 2 log10 units. The therapeutic advantage for i.p.-implanted L1210 of maintaining plasma concentrations of DSG was indicated further by infusion studies using s.c.-implanted Alzet osmotic pumps. Tumor burden was reduced by 3.5 and 6 log10 units following s.c. bolus treatments every 3 h on day 1 and a 24 h-infusion, respectively. The optimal infusion time for an infusion rate in mice of 179 mg/kg/day appeared to be 72 h. Pharmacokinetic studies following bolus i.v. injection revealed a rapid plasma clearance of parent drug (20.8 ml/min/kg) and a beta half-life of approximately 12 min. The bolus dose kinetics was used to predict the steady state plasma concentrations resulting from s.c. infusion; good agreement was observed between predicted values and experimental results. Based on these preclinical data, DSG has been developed to clinical trial. Initial Phase I protocols involve a 120-h infusion schedule.
ISSN:0008-5472
1538-7445